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EJNMMI Research
Published in: EJNMMI Research 1/2019

Open Access 01-12-2019 | Scintigraphy | Original research

HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor

Authors: Kakali De, Dibyanti Mukherjee, Samarendu Sinha, Shantanu Ganguly

Published in: EJNMMI Research | Issue 1/2019

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Abstract

Background

Among the many peptide receptor systems, gastrin-releasing-peptide (GRP) receptors, the mammalian equivalent of bombesin (BN) receptors, are potential targets for diagnosis and therapy of breast tumors due to their overexpression in various frequently occurring human cancers. The aim of this study was to synthesize and comparative evaluation of 99mTc-labeled new BN peptide analogs. Four new BN analogs, HYNIC-Asp[PheNle]BN(7-14)NH2, BN1; HYNIC-Pro-Asp[TyrMet]BN(7-14)NH2, BN2; HYNIC-Asp-Asn[Lys-CHAla-Nle]BN(7-14)NH2, BN3; and DOMA-GABA[Pro-Tyr-Nle]BN(7-14)NH2, BN4 were synthesized and biologically evaluated for targeted imaging of GRP receptor-positive breast-tumors.

Methods

Solid-phase synthesis using Fmoc-chemistry was adopted for the synthesis of peptides. BN1–BN4 analogs were better over the standard Gln-Trp-Ala-Val-Gly-His-Leu-Met-NH2 (BNS). Lipophilicity, serum stability, internalization, and binding affinity studies were carried out using 99mTc-labeled analogs. Biodistribution and imaging analyses were performed on MDA-MB-231 cell-induced tumor-bearing mice. BN-analogs induced angiogenesis; tumor formation and GRP-receptor-expression were confirmed by histology and immunohistochemistry analyses of tumor sections and important tissue sections.

Results

All the analogs displayed ≥ 97% purity after the HPLC purification. BN-peptide-conjugates exhibited high serum stability and significant binding affinity to GRP-positive tumor; rapid internalization/externalization in/from MDA-MB-231 cells were noticed for the BN analogs. BN4 and BN3 exhibited higher binding affinity, stability than BN1 and BN2. Highly specific in vivo uptakes to the tumor were clearly visualized by scintigraphy; rapid excretion from non-target tissues via kidneys suggests a higher tumor-to-background ratio. BN4, among all the analogs, stimulates the expression of angiogenic markers to a maximum.

Conclusion

Considering its most improved pharmacological characteristics, BN4 is thus considered as most promising probes for early non-invasive diagnosis of GRP receptor-positive breast tumors.
Appendix
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Literature
1.
Fani M, Maecke HR, Okarvi SM. Radiolabeled peptides: valuable tools for the detection and treatment of cancer.Theranostics. 2012;2:4181–501.
2.
Garayoa EG, Schweinsberg C, Maes V, Brans L., Blauenstein P, Tourwe DA, Schibli R, Schubiger P A. Influence of the molecular charge on the biodistribution of bombesin analogue labeled with the [99mTc(CO)3]-core. Bioconjug Chem. 2008;19:2409–2416.
3.
Reubi JC. Peptide receptors as molecular targets for cancer diagnosis and therapy. Endocr Rev. 2003;24:389–427.
4.
Zhang H, Schuhmacher J, Waser B, Wild D, Eisenhut M, Reubi J C, Maecke HR. DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumors. Eur J Nucl Med Mol Imaging. 2007;34:1198–1208.
5.
Karra SR, Gali RH, Katti KV, Hoffman TJ, Higginbotham C, Sieckman GL, Volkert WA. 99mTc-labeling and in vivo studies of a bombesin analogue with a novel water-soluble dithiadiphosphine-based bifunctional chelating agent. Bioconjug Chem. 1999;10:254–260.
6.
Retzloff LB, Heinzke L, Figureoa SD, Sublett SV, Ma L Sieckman, GL Rold, TL Santos, I. Hoffman TJ, Smith CJ. Evaluation of [99mTc-(CO)3-X-Y-Bombesin(7-14)NH2]conjugates for targeting gastrin-releasing peptide receptors overexpressed on breast carcinoma. Anticancer Res. 2010;30:19–30.
7.
Okarvi SM. Peptide-based radiopharmaceuticals: future tools for diagnostic imaging of cancers and other diseases. Med Res Rev 2004;24:357–397.
8.
Parry JJ, Andrews R, Roger BE. Micro-PET imaging of breast cancer using radiolabeled bombesin analogs targeting the gastrin-releasing peptide receptor. Breast Cancer Res Treat. 2007;101:175–183.
9.
De K, Banerjee I, Misra M. Radiolabeled new somatostatin analogs conjugated to DOMA chelator used as targeted tumor imaging agent: synthesis and radiobiological evaluation. Amino Acids. 2015;47:1135–1153.
10.
Breeman WA, de Jong M, Erion JL, Bugaj JE, Srinivasan A, Bernard BF. Preclinical comparison of (111)In-labeled DTPA or DOTA-bombesin analogs for receptor-targeted scintigraphy and radionuclide therapy. J Nucl Med. 2002;43:1650–1656.
11.
Reubi JC. Gugger M, Waser B. Co-expressed peptide receptors in breast cancer as a molecular basis for in vivo multireceptor tumor targeting. Eur J Nucl Med. 2002;29:855–862.
12.
Carlesso FN, Fuscaldi LL, Araujo RS, Teixeira CS, Oliveira MC, Fernandes SOA, Cassali GD, Reis DC, Barros ALB, Cardoso VN. Evaluation of 99mTc-HYNIC-βAla-Bombesin(7-14) as an agent for pancreas tumor detection in mice. Braz J Med Biol Res. 2015;48:923–928.
13.
Jamous M, Tamma ML, Gourni E, Waser B, Reubi JC, Maecke HR, Mansi R. PEG spacers of different length influence the biological profile of bombesin-based radiolabeled antagonists. Nucl Med Biol. 2014;41:464–470.
14.
de Barros, AL, Mota LG., Ferreira CA, Oliveira MC, Goes AM, Cardoso VN. Bombesin derivative radiolabeled with technetium-99m as agent for tumor identification. Bioorg Med Chem Lett. 2010;20:6182–6184.
15.
Valverde IE, Vomstein S, Mindt TL. Toward the optimization of bombesin-based radiotracers for tumor targeting. J Med Chem 2016;59:3867–3877.
16.
Ranyuk E, Cauchon N, Klarskov K, Guérin B, Van JEL. Phthalocyanine-peptide conjugates: receptor-targeting bifunctional agents for imaging and photodynamic therapy. J Med Chem. 2013;56:1520−1534.
17.
Nock BA, Nikolopoulou A, Galanis A, Cordopatis P, Waser B, Reubi JC, Maina T. Potent bombesin-like peptides for GRP-receptor targeting of tumors with 99mTc: a preclinical study. J Med Chem. 2005;48:100−110.
18.
Good S, Walter MA, Waser B., Wang XJ, Muller-Brand J., Behe M P, Reubi JC, Maecke HR. Macrocyclic chelator-coupled gastrin-based radiopharmaceuticals for targeting of gastrin receptor-expressing tumours. Eur J Nucl Med Mol Imaging. 2008;35:1868−1877.
19.
Shirmardi SP, Gandomkar M, Mazidi M. Synthesis and evaluation of a new bombesin analog labeled with 99mTc as a GRP receptor imaging agent. J Radioanal Nucl Chem. 2011;288:327−335.
20.
Pujatti PB, Foster JM, Chantelle CF, Hudson D, Burnet JC, Pasqualoto KFM, Mengatti J, Mather SJ, de Araújo EB, Sosabowski JK. Evaluation and comparison of a new DOTA and DTPA-bombesin agonist in vitro and in vivo in low and high GRPR expressing prostate and breast tumor models. Appl Rad Isotopes. 2015;96:91−101.
21.
Liu Y, Hu X, Liu H, Bu L, Ma X, Cheng K, Li Tian JM, Zhang H, Cheng ZA. A comparative study of radiolabeled bombesin analogs for the PET imaging of prostate cancer. J Nucl Med. 2013;54:2132–2138.
22.
Okarvi SM, Jammaz I Al. Preparation and evaluation of bombesin peptide derivatives as potential tumor imaging agents: effects of structure and composition of amino acid sequence on in vitro and in vivo characteristics. Nucl Med Biol. 2012;39:795–804.
23.
Ferreiraa C de A, Fuscaldib LL, Townsendc DM, Rubellod D, de Barrosb ALB. Radiolabeled bombesin derivatives for preclinical oncological imaging. Biomed. Pharmacotherapy. 2017;87:58–72.
24.
De K, Bhowmik A, Behera A, Banerjee I, Ghosh M K, Misra M. Synthesis, radiolabeling, and preclinical evaluation of a new octreotide analog for somatostatin receptor-positive tumor scintigraphy. J Pept Sci. 2012;18:720–730.
25.
De K, Banerjee I, Sinha S, Ganguly S. Synthesis and exploration of novel radiolabeled bombesin peptides for targeting receptor positive tumor. Peptides. 2017;89:17–34.
26.
Zhang H, Schuhmacher J, Waser B, Wild D, Eisenhut M, Claude J, Maecke HR. DOTA-PESIN, a DOTA-conjugated bombesin derivative designed for the imaging and targeted radionuclide treatment of bombesin receptor-positive tumours. Eur J Nucl Med Mol Imag. 2007;34:1198–1208.
27.
Gandomkar M, Najafi R, Shafiei Mazidi M, Ebrahimi SES. Preclinical evaluation of [99mTc/EDDA/tricine/HYNIC0, 1-NaI3, Thr8]-octreotide as a new analogue in the detection of somatostatinreceptor-positive tumors. Nucl Med Biol. 2007;34:651–657.
28.
Chen X, Park R, Hou Y, Tohme M, Shahinian AH, Bading JR, Conti PS. Micro-PET and autoradiographic imaging of GRP receptor expression with 64Cu-DOTA-[Lys3]bombesin in human prostate adenocarcinoma xenografts. J Nucl Med 2004;45:1390–1397.
29.
Akla B, Monteil J, Paraf F, Sturtz F, Rigaud MA. A new peritoneal carcinomatosis model in cyclosporine immunosuppressed rats. Anticancer Res. 2003;23:3761–3766.
30.
Fingert HJ., Treiman A, Pardee AB. Transplantation of human or rodent tumors into Cyclosporine - treated mice: a feasible model for studies of tumor biology and chemotherapy. Proc Natl Acad Sci. 1984;81:7927–7931.
31.
Min K, Ji B, Zhao M, Ji T, Chen B, Fang X, Ma, Q. Development of a radiolabeled peptide-based probe targeting MT1-MMP for breast cancer detection. Plos One. 2015;10:e0139471.
32.
Iorns E, Drews-Elger K, Ward TM, Dean S, Clarke J, Berry D, El Ashry D, Lippman MA. A new mouse model for the study of human breast cancer metastasis. Plos. One. 2012;7:e47995.
33.
Rick FG, Buchholz S, Schally AV, Szalontay L, Krishan A, Datz C, Stadimayr A, Aigner E, Perez R, Seitz S, Block NL, Hohla F. Combination of gastrin-releasing peptide antagonist ith cytotoxic agents produces synergistic inhibition of growth of human experimental colon cancers. Cell cycle. 2012;11:2518–2525.
34.
Park HJ, Kim SR, Kim MK, Choi KS, Jang HO, Yun I l, Bae SK, Bae M K. Neuromedin B receptor antagonist suppresses tumor angiogenesis and tumor growth in vitro and in vivo. Cancer Lett. 2011;312:117–127.
35.
Gao D, Bambang I F, Putti TC, Lee YK, Richardson DR, Zhang D. ERp29 induces breast cancer cell growth arrest and survival through modulation of activation of p38 and upregulation of ER stress protein p58IPK. Lab Invest. 2012;92:200–213.
36.
Marsden CG, Wright MJ, Carrier L, Moroz K, Pochampally R, Rowan BG. A novel in vivo model for the study of human breast cancer metastasis using primary breast tumor-initiating cells from patient biopsies. BMC Cancer. 2012;12:10.
37.
Bella RL, Garcia-Garayoa E, Bahler M, Blauenstein P, Schibli Conrath RP, Tourwe D, Schubiger PA. A 99mTc(I)-postlabeled high affinity bombesin analogue as a potential tumor imaging agent. Bioconjug Chem. 2002;13:599–604.
38.
Branco de Barros AL. Radiolabeled peptides as imaging probes for cancer diagnosis. J Mol Pharm Org Process Res. 2014;2:e115.
39.
Schroeder RPJ, van Weerden WM, Bangma C, Krenning EP, de Jong M. Peptide receptor imaging of prostate cancer with radiolabelled bombesin analogues. Methods. 2009;48:200–204.
40.
Garcia Garaypoa E, Schweinsberg C, Maes V, Brans Blauenstein LP, Tourwe DA, Schibli RP. August Schubiger. Influence of the molecular charge on the biodistribution of bombesin analogues labeled with the [99mTc(CO)3]-core. Bioconjug Chem. 2008;19:2409–2416.
41.
Smith CJ, Volkert WA, Hoffman T. Radiolabeled peptide conjugates for targeting of the bombesin receptor superfamily subtypes. J Nucl Med Biol 2005;32:733–740.
Metadata
Title
HYNIC and DOMA conjugated radiolabeled bombesin analogs as receptor-targeted probes for scintigraphic detection of breast tumor
Authors
Kakali De
Dibyanti Mukherjee
Samarendu Sinha
Shantanu Ganguly
Publication date
01-12-2019
Publisher
Springer Berlin Heidelberg
Keyword
Scintigraphy
Published in
EJNMMI Research / Issue 1/2019
Electronic ISSN: 2191-219X
DOI
https://doi.org/10.1186/s13550-019-0493-x

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